Principal Investigator/Program Director (Last, first, middle): Kwong, Raymond RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? l Yes m No 1.a. If YES to Human Subjects Is the IRB review Pending? l Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 00000484 2. * Are Vertebrate Animals Used? m Yes l No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes m No IACUC Approval Date: Animal Welfare Assurance Number 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 7281-ProjectSummary.pdf Mime Type: application/pdf 7. * Project Narrative 2576-ProjectNarrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 7413-Bibliography.pdf Mime Type: application/pdf 9. Facilities &Other Resources 708-Facilities.pdf Mime Type: application/pdf 10. Equipment 7422-Equipment.pdf Mime Type: application/pdf 11. Other Attachments 3210-Yan_Circulation2006.pdf Mime Type: application/pdf 11. Other Attachments 3122-CIRCULATIONAHA.105.570648v1M.pidmf e Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Kwong, Raymond Project Summary/Abstract The incidence of sudden cardiac death (SCD) after myocardial infarction (MI) has remained unchanged and is most significant in the first year after MI. The marked cellular anisotropy observed in the peri-infarct zone has reported to be a potential cause of ventricular arrhythmias. Cardiac magnetic resonance imaging (CMR) can characterize myocardial tissue changes and ventricular function after MI. Recently, our group demonstrated the clinical feasibility of quantifying the extent of the peri-infarct zone using contrast-enhanced CMR (PIZCMR) and also reported its strong prognostic association with post-MI all-cause mortality.(3) In a study of 144 patients with MI, we used a novel automated technique to quantify the late-enhancing region into the core and peri-infarct (PIZCMR) regions based on signal-intensity threshold (>3SDs and 2 to 3 SDs above remote normal myocardium, respectively). PIZCMR was quantified in absolute mass (MDEperiphery) and as a percentage of the total enhancing region (%MDEperiphery). We found that %MDEperiphery was a powerful predictor of all-cause mortality incremental to patient age and left ventricular ejection fraction (LVEF). With recent advances in digital signal processing, microvolt T-wave alternans (MTWA) in detecting unstable electrophysiological substrate that exposes post-MI patients to SCD. On the therapeutic side, strong experimental evidence of membrane stabilization effects of omega-3 polyunsaturated fatty acids ([unreadable]-3 FA) against malignant arrhythmias has been substantiated by a remarkable reduction of SCD in patients with coronary artery disease in large-scale randomized clinical trials. These published findings provide the impetus for the present proposal to elucidate the pathogenic basis underlying the observed prognostic association of PIZCMR and post-MI mortality. The central hypothesis of this proposal is that PIZCMR contains the structural and electrical substrate essential for the generation of reentrant ventricular tachycardia, and that its healing can be promoted by [unreadable]-3 FA, translating to a reduced risk of SCD and/or significant ventricular arrhythmic events requiring defibrillation. Accordingly, we plan to randomized 414 patients with acute MI to supplementation with either [unreadable]-3 FA (4 gm/day for 9 months) or placebo is designed to test the hypotheses that 1) Direct myocardial quantitation of PIZCMR provides incremental prognostic association, beyond LVEF and MTWA, with MACE;2) Oral supplementation with [unreadable]-3 FA can beneficially modify the prognostic association of the PIZCMR with MACE;3) Patients who suffered an acute MI and have a large PIZCMR, exhibit concomitant electrical heterogeneity by MTWA;and 4) Oral [unreadable]-3 FA supplementation to patients who suffered an acute MI, reduces the myocardial extent of PIZCMR and normalizes MTWA, compared to the placebo control group. Project Description Page 6 Raymond Y. Kwong, MD 2/5/07 2:09 AM 30 Page of 38